ES2734510T3 - Transdermal administration - Google Patents

Abstract

A contraceptive method, comprising: (A) consecutively applying three transdermal hormone treatment devices on a woman's skin during a 3-week treatment interval, applying each device for 1 week, and each device comprises an effective amount of one progestogen and an estrogen followed by a rest interval of 1 week; and (B) applying a resting interval device for at least a portion of the resting interval, wherein the resting interval device comprises low dose progestin and low dose estrogen.

Description

DESCRIPTION

Transdermal administration

Field of the Invention

[0001] This invention relates to the field of transdermal administration, in particular, of hormones.

Background of the invention

[0002] Progestins, or combinations of progestins and estrogens, are used to inhibit ovulation and to induce other physiological changes in the female reproductive system and, therefore, to reduce the risk of pregnancy.

[0003] Several dosage regimens have been used to administer such hormones. These include, for example, the oral self-administration of a progestogen and an estrogen for 21 days, followed by a 7-day "rest" interval, during which the woman usually experiences bleeding from extraction (ie, menstrual). . Other dosage regimens may also be used, including dosage regimens that involve longer durations of the administration of a progestogen and dosage regimens that involve the use of low dose hormones during an untreated interval.

[0004] An important aspect of any effective contraceptive dosing regimen is that the regimen is convenient in order to facilitate compliance and that the doses administered are effective in preventing or reducing the risk of pregnancy without exposing women to unnecessary risks of side effects. Side effects may include adverse events related to hormones and irregularities in the control of the cycle, in particular "significant" bleeding.

[0005] A transdermal hormone delivery device for the administration of a progestin and an estrogen through a patch, and a combination of skin permeation enhancer for use therein, are described, for example, in US 7,045,145 and US 20040054901.

[0006] US 7045145 B1, WO 2005/002482 A1, US 6,251,956 B1, LaGuardia et al., 2005, Fertility and Sterility, 83 (6): 1875-1877, US 2005/142175 A1, and US 2005/032764 A1 disclose contraceptive methods by applying a transdermal administration system for delivery of an administration and an estrogen. These documents reveal that, in a typical 28-day cycle, transdermal dosing units are administered over a period of 21 days, followed by 7 days without administration of a dosing unit. Optionally, the dosage units are administered over a period of 28 days, which provides continuous transdermal hormone dosing.

[0007] US 2007/111975 A1 describes an up-dose extended cycle regime in which an estrogen and a progestin are administered for a period of more than 30 or 31 consecutive days, optionally followed by a period without hormones or estrogen administration for a period of 2 to 10 consecutive days. Summary of the Invention

[0008] The invention provides a dosage regimen for the administration of a progestin and an estrogen. More specifically, the invention relates to a contraceptive method, that is, that reduces the risk of pregnancy, in a woman comprising, during a 28-day treatment cycle comprising a treatment interval and a rest interval, (A ) the consecutive application of three transdermal hormonal treatments devices to a woman's skin during a 3 week treatment interval, applying each device for 1 week, and each device comprises an effective amount of a progestogen and an estrogen followed by a range of 1 week break; and (B) applying a rest interval device for at least a part of the rest interval, wherein the rest interval device comprises low dose progestin and low dose estrogen.

[0009] The invention also provides a kit, comprising (a) 3, or a multiple of 3, transdermal hormone delivery treatment devices, each treatment device comprising a progestin and an estrogen in amounts sufficient to reduce the pregnancy risk, and each device intended for use for 1 week; (b) 1, or the same multiple of 1, rest interval devices, each rest interval device comprising low dose progestin and low dose estrogen; and (c) instructions for use in a 28-day treatment cycle.

Brief description of the figures

[0010] Figure 1 illustrates serum hormone concentrations during and after a single treatment cycle comprising a treatment interval of 21 or 24-1 / 2 days with or without a patch containing hormone in the rest interval The figures have been drawn at 31 days for illustrative purposes only and do not illustrate serum hormone concentrations during a subsequent treatment cycle. Specifically:

Figure 1a illustrates serum EE concentration levels for 31 days, as a result of the administration of 7 patches, each for 3-1 / 2 days. Figure 1b illustrates the levels of serum EE concentration for 31 days as a result of the administration of 7 patches, each for 3-1 / 2 days, followed by the administration of a rest interval device (1/2 patch) for 3-1 / 2 days. Figure 1c illustrates the levels of serum EE concentration for 31 days, as a result of the administration of 3 patches, each for 7 days. Figure 1d illustrates serum EE concentration levels for 31 days as a result of the administration of 3 patches, each for 7 days, followed by the administration of a rest interval device (1/2 patch) for 7 days.

Figure 2 illustrates an exploded cross-section of an illustrative dermal release system of the invention.

Detailed description

[0011] According to illustrative embodiments, in an individual, multiple treatment range, for example, six or seven transdermal hormone delivery devices, ie "patches," are applied consecutively to a woman's skin to administer a progestin and, optionally, an estrogen to prevent, that is, reduce the risk of pregnancy after sexual intercourse. In illustrative embodiments of the invention, it is intended that each patch be used during the 1/2 week, that is, for 3 to 4 days, for example, 3-1 / 2 days. Therefore, the total treatment interval is 6 multiplied by 1/2 week, that is, 3 weeks, or 7 multiplied per week, that is, 3-1 / 2 weeks. Each period of the 1/2 week is about 3 to about 4 days. For example, a single 1/2 week device can be used for 2-1 / 2 or 3 days of a given week, in which case the other 1/2 week device would be used for 4-1 / 2 or 4 days of that week, respectively, or each device can be used for 3-1 / 2 days each.

[0012] According to another illustrative embodiment, in a range of individual treatment, four transdermal hormone delivery devices, ie "patches," are used to administer a progestin and, optionally, an estrogen to a woman for Avoid conception. Three of the patches are designed to be used for 1 week each, while the remaining patch is used for week 1/2. Therefore, the total treatment interval is 3 multiplied by 1 week, that is, 3 weeks, plus 1 multiplied by 1/2 week, that is, week, which is equivalent to 3-1 / 2 weeks. The patch used for week 1/2 may be the same as the 7 day patch or it may have a reduced amount of hormone to account for the shorter period of use.

[0013] In any case, at the end of each treatment interval, a rest interval of 1/2 or 1 week follows, after the woman resumes treatment on day 29, that is, day 1 of the cycle next. As explained below, each 1/2 week period is about 3 to about 4 days. For example, a single 1/2 week device can be used for 2-1 / 2 or 3 days of a given week, in which case the other 1/2 week device would be used for 4-1 / 2 or 4 days of that week, respectively, or each device can be used for 3-1 / 2 days each. Similarly, each one-week period can be 6, 6-1 / 2, 7-1 / 2 and 8 days, although it is preferable to arrange one day per week, so that one week is 7 days.

[0014] The illustrative regimes described above are summarized in the following table.

[0015] A woman may choose to start using the first patch of the first treatment interval at or around the first patch. The day of the woman's period, that is, on the first day of menstrual bleeding. In this case, the woman can use a longer or shorter initial treatment interval or an initial rest interval, in order to put it into a schedule that is convenient for her.

[0016] Alternatively, a woman may start wearing patches on a different day, in which case, the first treatment interval may be, but is not necessarily adjusted to end on Day 28 of the woman's menstrual cycle, that is, 28 days after the first day of the most recent period of woman's menstrual bleeding. In such illustrative embodiments of this invention, for example, a woman applies a first patch on a Sunday morning and removes it and applies a second patch 3-1 / 2 days later, that is, on the afternoon of the following Wednesday, and so on, as illustrated below:

Treatment Interval:

[0017]

Patch 1 - applied on Sunday morning; removed on Wednesday afternoon,

Patch 2 - applied on Wednesday afternoon; removed Sunday morning,

Patch 3 - applied on Sunday morning; removed on Wednesday afternoon,

Patch 4 - applied Wednesday afternoon; removed Sunday morning,

Patch 5 - applied on Sunday morning; removed on Wednesday afternoon,

Patch 6 - applied Wednesday afternoon; removed Sunday morning

Patch 7 - applied on Sunday morning; removed on Wednesday afternoons,

Rest interval: from Wednesday afternoon to Sunday mornings

Repetition

[0018] Such a regimen, beginning with a first treatment on a Sunday night (instead of on a Sunday morning, as illustrated above), is illustrated graphically in the following tables that show an illustrative calendar for two cycles of consecutive treatment. In these tables, patches are indicated by superscript or subscript numbers 1 through 7, with superscript values indicating application in the morning and subscript values indicating application at night. "RI" indicates the start of the rest interval.

Illustrative regime of seven patches of 3-1 / 2 days

Treatment cycle 1

[0019]

Treatment cycle 2

[0020]

[0021] In an alternative embodiment of the invention, a user applies six half-week patches during a 21-day treatment interval, followed by a 7-day rest interval, as illustrated below. Illustrative regimen of six patches of 3-1 / 2 days

Treatment cycle 1

[0022]

Treatment cycle 2

[0023]

[0024] In a variation of the regimens described above, in a range of individual treatment, three transdermal hormone delivery devices, ie "patches", are used to administer a progestin and, optionally, an estrogen to a Woman to avoid conception. Each patch is designed to be used for 1 week. Therefore, the total treatment interval is 3 times 1 week, that is, 3 weeks. In such an embodiment, a fourth treatment device is applied for a week or a rest interval device is applied to administer a low dose hormone during all or a part of the rest interval, for example, low dose progestin, estrogen of low dose or both. "Low dose" means a dose that is not effective for contraception if used during a treatment interval.

[0025] The following table illustrates the use of three 1-week treatment devices and a rest interval device (RI +), which contains the low dose hormone, followed by a rest interval without a rest interval device ( RI-)

Illustrative regime of three 7-day patches

Treatment cycle 1

[0026]

Treatment cycle 2

[0027]

[0028] It will be appreciated that in each of the above illustrations, the first day of each treatment cycle, that is, the first day of the application of a new device, is designated as Day 1. The Day could have been designated 0 (as shown in Figure 1, discussed below), in which case, all other numbers of days would be reduced by one. It will also be appreciated that the first application in this illustration is made in the afternoon / evening of Day 1, shown here as Sunday, but that the first application can also be made on a Sunday morning or in the morning, in the afternoon or late of any other day of the week.

[0029] It should also be appreciated that although the above illustrations use 3-1 / 2 days as a 1/2 week interval, it is also possible according to this invention to use a patch for 2-1 / 2 to 4-1 / 2 days, for example, 3-4 days per week, and another patch for the rest of the week, provided that two successive week periods total approximately seven days. This is illustrated in the following table for seven patches of A week.

Illustrative regimen of patches of seven and a half weeks

Treatment cycle 1

[0030]

Treatment cycle 2

[0031]

[0032] In other embodiments, each week is set at 3-1 / 2 days.

[0033] A one-week device may be used in a similar manner, for example, for 6, 6-1 / 2, 7, 7-1 / 2 or 8 days, although it is preferable to fix it one day per week, such that a Week is 7 days.

[0034] In embodiments, only one progestin is administered during treatment intervals. In other embodiments, the progestin is administered in combination with an estrogen during the treatment intervals, for all or a portion of each treatment interval. In any case, a progestin or an estrogen or both can be administered, but not necessarily, during all or a part of the rest interval, as described below.

[0035] The amount of the hormone in each treatment device, for example, every 3-1 / 2 day patch or 7 day patch, can be varied from patch to patch or week to week, to provide a treatment regimen multiphase. For example, the amounts of hormone may be varied to provide a three-phase administration regimen such as, for example, the three-phase oral contraceptive described in US 6,214,815 (Ortho-McNeil). Either or both of the progestin and estrogen can be varied (or maintained) independently of each other. Alternatively, the amount of progestin and estrogen can be the same in all patches used in a given treatment cycle or in all treatment cycles.

[0036] It is desirable that each treatment device results in an average progestin serum concentration level equivalent to at least about 750 pg / ml of levonorgestrel during the entire treatment interval. In some embodiments, the average level of serum progestin concentration is equivalent to at least about 500 pg / ml of levonorgestrel during week 1 of the treatment interval and / or at least approximately 750 pg / ml during week 2 and week 3 of each treatment interval, it being understood, however, that such levels may not be reached during the entire first treatment cycle. In particular, for example, such levels may not be reached during the first week of the first treatment cycle.

[0037] In addition, serum concentrations of a progestin, as well as an estrogen, may vary from patient to patient. Therefore, when considering the average serum concentrations reached during treatment intervals, it is useful to refer to a population of subjects, for example, 10 or more, 25 or more, 50 or more, 75 or more, or 100 or more. Therefore, the concentration values and the peak / depression ratios expressed in this document can be achieved in a population of subjects, but not necessarily in each subject within a given population.

[0038] The amount of estrogen administered during each treatment interval may be an amount that results in serum concentration levels equivalent to about 5 to about 80, for example, about 15 to about 65, pg / ml ethinylestradiol throughout the treatment. treatment range, or from about 20 to about 30 pg / ml. Serum concentration levels that average between 20 and 30. The equivalent of ethinyl estradiol pg / ml can be achieved during week 2 and week 3 of each treatment interval.

[0039] According to the invention, doses of the low hormone (s) (or lower (s)) are administered during all or part of the rest interval. The amount of hormone administered during the rest interval is not more than 80%, for example, from about 20% to about 80% of the amount administered during the treatment interval. For example, the amount of hormone (s) administered during the rest interval may be about 3/4, about 2/3, about 1/2, about 1/3 or about 1/4 of the amount administered during an amount equivalent time during the treatment interval. Such an amount may attenuate, that is, decrease the severity of menstruation symptoms, which may include excessive vaginal bleeding, changes in mood, headaches, dysmenorrhea and other symptoms associated with the withdrawal of hormones, especially withdrawal. Sudden hormones, or others.

[0040] Such a rest interval patch, or rest interval device, may conveniently be made in the same manner as the treatment device, but with a reduced amount of the hormone (s). The amount of hormone (s) can be reduced, for example, by reducing the size of the patch. For example, if a treatment patch has a surface area of 20 cm2 and it is desired to administer 50% of the hormones during the rest interval, the rest interval device may be the same as the treatment interval device but reduced in size so that they have an area of 10 cm2. Said rest interval device could be called "half patch." Similarly, a "quarter patch" could be administered to administer 25% of the hormones, or a patch of any other fraction of the size of the treatment patch. Alternatively, the size (surface area) of the rest interval device may be the same as the size of the treatment device, in which case it would be loaded with reduced amounts of hormones and / or enhancers.

[0041] The rest interval device can be used for any part or all of the rest interval. Thus, for example, a half patch can be used for the entire rest interval.

[0042] Figure 1 shows the illustrative levels of serum hormone concentration for 31 days. In accordance with the practice of this invention, of course, a new device would be applied on day 29.

[0043] As illustrated in Figure 1, the patches can be designed in order to deliver varying amounts of hormone (s) during the wear period of each patch, so that there is a peak level of serum concentration that occurs after the patch is applied and a serum concentration level that occurs at the time the patch is removed. This feature can be used in a useful way to administer an amount of progestin or estrogen, or both, during the rest interval that decreases as the end of the rest interval approaches, so that the amount of hormone released at the end of the interval of rest decreases in relation to the maximum levels during wear of the rest interval device and, in some embodiments, in relation to serum concentration levels on the day the rest interval device is applied. Such a device can be referred to as a descending dose device.

[0044] The use of said rest interval device can have several advantages. In one embodiment, the rest interval device is a placebo and is used as a matter of convenience, for example, so that the woman has a habit of removing and applying a patch every 3 to 12 days or every 7 days. In another embodiment, the low dose hormone is administered in such a way that the woman experiences menstruation, but with attenuated symptoms. In such an embodiment, too, serum hormone concentration levels are adjusted gradually instead of "all or nothing."

[0045] A 3-1 / 2-day patch may be smaller than a 7-day patch, therefore, which is less noticeable to the user and the people around him. Adhesion requirements are also alleviated because the patch is smaller and because it does not need to remain connected throughout the week. If a 3-1 / 2 day patch is evicted, there will only be a short period of time before the next patch is applied. A 3-1 / 2-day patch may allow a pharmacokinetic profile (PK) with peaks and valleys during each period of use, that is, during each 3-1 / 2-day treatment period, but such peaks and valleys may be more soft in relation to a 7 day patch. Thus, for example, the maximum serum hormone concentrations during the period of time when a single treatment device (other than the first device) is used may be at least about 1.1 times the minimum levels, or at least about 1, 25 times more minimum levels, but it can also be no more than about twice the minimum levels, or no more than about 1.8 times the minimum levels, or no more than about 1.5 times the minimum levels. Figure 1 illustrates said PK profiles across the peak. Said PK profile can be achieved during a complete treatment interval or for at least a wear interval, for example, the third week, the second half of the second or third week, or at least 2 weeks, for example, the weeks second and third, of each treatment interval.

[0046] Any transdermal hormone delivery device that administers a progestin and, optionally, an estrogen, in amounts effective to effect contraception, that is, to prevent pregnancy, can be used in the practice of the invention. "Preventing pregnancy" does not necessarily mean that such devices are 100% effective in preventing pregnancy in all cases, but such devices may have at least about the same contraceptive efficacy as currently available oral contraceptives. US 5,876,746 (Cygnus) describes a transdermal hormone delivery device to prevent pregnancy that releases 17-deacetyl norgestimate and ethinylestradiol (Cygnus) and is marketed as Ortho Evra (r) (norelgestromin / ethinyl estradiol transdermal system) . As shown in the prescription information, Ortho Evra provides a more or less "flat" supply, that is, no or only a peak PK profile through each wear period of a single patch.

[0047] It is also described herein that it comprises a kit of multiple patches each intended to be worn for 1/2 weeks (2-1 / 2 to 4-1 / 2 days) or 1 week (6-8 days). For example, said kit may comprise treatment devices of seven and a half weeks, or some multiples of 7, for example, 14, 21, 28, 35 or 42 treatment devices. Or, for example, said kit may comprise treatment devices of six and a half weeks, or some multiples of 6, for example, 12, 18, 24, 30, 36, 42,48, 54, 60, 66 or 72 devices of treatment. Or, for example, said kit may comprise three 7-day treatment devices, or some multiples of 3, for example, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 or 36 devices of treatment, and a treatment device of one week for every three devices of a week. In each case, the kit would include instructions for the use of the devices according to the method of the invention.

[0048] Such a kit may also comprise rest interval devices, which may be placebos (ie, non-hormonal) or low-dose hormone devices, as discussed above. For example, a kit for a regime of seven patches / cycles of treatment may comprise forty-two half-week treatment devices and six rest interval devices; a kit for a regimen of six patches / treatment cycle may comprise seventy-two half-week treatment devices and twelve rest interval devices; A kit for a 3-patch regime / treatment cycle may comprise nine 7-day treatment devices and three rest interval devices; etc.

[0049] Such rest interval devices can be clearly indicated as rest interval devices, directly or in individual patch packages, such as by size, color, shape, or marks, to avoid confusion with the treatment devices. If a profile of administration of multiphase hormones is desired, each treatment device can be marked, directly or in an individual patch package, to minimize the risk of a user applying patches out of order.

[0050] Figure 1 illustrates the projected levels of ethinylestradiol (EE) serum concentration resulting from patch administration, as described in US 7,045,145 and US 20040054901 and later in this document. The data in Figure 1 are illustrative and do not show the effect of applying a new patch on Day 29. The data is projections calculated on the basis of actual human body skin flow data obtained using a device loaded with a matrix polymeric comprising LNG and EE, substantially as described below, and having an area of skin contact of approximately 9.4 cm2. The projections are calculated using an approximate in vivo elimination rate for e E. Figures 1a and 1b show the EE levels on each of Days 1 to 28, with a first patch of 3-1 / 2 days on the Day 0 and subsequent patches on Days 4, 7, 11, 14, 18 and 21. Figures 1c and 1d show the levels of EE on each of days 1 to 28, with a first 7-day patch applied on the day 0 and subsequent patches on days 7 and 14. Figures 1b and 1d show the effects of administering a rest interval patch on days 24 to 28, said rest interval device is 1/2 of the patch size of treatment but, otherwise, identical to it.

[0051] A similar pattern of peaks / valleys can be obtained with progestins, e.g. eg, LNG.

[0052] Note that because these data are projected from skin flow data, actual results will vary, depending, for example, on the skin surface area of the patch used, the hormone concentration (s ) and the effectiveness of the skin permeation enhancer.

[0053] An illustrative device that can be used in the practice of the present invention is illustrated in Figure 2. With reference to Figure 2, this illustrative device comprises 4 layers. One is the AI layer (6). The second is a release liner (4). The third is an internal backing layer (5). The fourth is an overlay, which, in this illustrative device, comprises three component layers (1, 2, 3), referred to hereinafter as, respectively, a PSA layer (3), an intermediate layer (2) and a overlay coating or coating coating (1). The overlay can also be described as comprising a layer of PSA (3) and an overlay cover (1,2). In any case, a feature of this device is the formation of a seal between the PSA layer (3) of the overlay (1, 2, 3) and the release liner (4).

AI layer

[0054] Layer 6 comprises AI and carriers comprising skin permeation enhancers, a humectant / plasticizer and a PSA matrix. AI comprises a progestin, for example, levonorgestrel, and an estrogen, for example, ethinyl estradiol or 17-p estradiol.

[0055] Skin permeation enhancers : A combination of improving skin permeation agents is employed comprising a mixture of (1) a pharmaceutically acceptable organic solvent, such as dimethyl sulfoxide (DMSO), alcohol ester ( 2) fatty (C8-C20) of a hydroxy acid, such as lauryl lactate, (3) a lower alkyl ester (C1-C4) of a hydroxy acid, for example, ethyl lactate, and (4) a C6-C18 fatty acid , such as capric acid. In specific embodiments, the fatty alcohol ester of lactic acid is lauryl lactate and the lower alkyl ester of lactic acid is ethyl lactate. A medium to long chain fatty acid can be used in the formulation of the skin permeation enhancer among the skin permeation enhancers. Capric acid has been used, but other saturated or unsaturated C6-C18 fatty acids include, but are not limited to, caproic acid, capritic acid, lauric acid and myristic acid.

[0056] In a particular embodiment, the pharmaceutically acceptable organic solvent is DMSO. Other organic solvents include, but are not limited to branched or unbranched C1-C8 alkyl, such as ethanol, propanol, isopropanol, butanol, isobutanol, and the like, as well as azone (laurocapram: 1-dodecyl hexahydro-2H-azepin-2- ona) and methylosulfonylmethane.

[0057] The fatty alcohol ester of a hydroxy acid may be a fatty alcohol ester of lactic acid, such as lauryl lactate. However, other hydroxy acids and fatty alcohols can be used. Alternative hydroxy acids include, but are not limited to, alpha-hydroxy acids such as glycolic acid, tartaric acid, citric acid, malic acid and mandelic acid, as well as beta-hydroxy acid, salicylic acid. Alternative fatty alcohols include any saturated or unsaturated C8-C20 fatty alcohol, such as myristyl, palmityl or oleyl alcohols, to name a few.

[0058] The lower alkyl ester of hydroxy acid may also use lactic acid, and may be, for example, ethyl lactate. However, other hydroxy acids, such as glycolic acid, tartaric acid, citric acid, malic acid, mandelic acid and salicylic acid, can also be used. In addition, isopropylmistic acid (IPM) can be used as a substitute for the lower alkyl ester of the hydroxy acid.

[0059] Hormones: LNG is a potent progestogen on a dose-by-weight basis, which is an important factor, since progestins often exhibit a much lower degree of transdermal absorption than estrogens. Other progestins that could be used in part or in total are norgestrel, norgestimate, desogestrel, signodene, norethindrone, norethinodrel, hydrogesterone, ethinodiol diacetate, hydroxyprotesterone caproate, medroxyprogesterone acetate, norindindone acetate, progesterone, alcoholistester, bioistester acetate, biocomester acetate transdermally absorbable. These include biocompatible progestin derivatives that are absorbed transdermally, some of which, advantageously, are bioconvertible after transdermal absorption of the original progestin. Progestin and other selected hormones preferably have high compatibility with each other.

[0060] For combinations of progestin with estrogen, the synthetic hormone EE is particularly suitable, although natural estrogens or other analogs may be used. This hormone can be administered transdermally together with the particularly suitable progestin, levonorgestrel, at desirable daily rates for both hormones. EE and LNG are compatible and can be dispersed in the adhesive polymer formulation.

[0061] Derivatives of 17 p-estradiol that are biocompatible, capable of being transdermally absorbed and preferably bioconvertible to 17 p-estradiol can also be used, if the amount of absorption meets the required daily dose of the estrogen component and if the components Hormonals are compatible. Such estradiol derivatives include esters, mono- or di-esters. The monoesters can be 3 or 17 esters. The estradiol esters may, illustratively, be estradiol-3, 17-diacetate; estradiol-3-acetate; estradiol 17-acetate; estradiol-3, 17-divalerate; estradiol-3-valerate; estradiol-17-valerate; esters of 3-mono-, 17-mono- and 3.17-dipivylated; esters of 3-mono-, 17-mono- and 3.17-dipropionate; esters of 3-mono-, 17-mono- and 3.17-dicyclo pentyl propionate; cypionate, heptanoate, benzoate and corresponding similar esters; ethinylestradiol; estrone and other estrogenic steroids and derivatives thereof that are transdermally absorbable.

[0062] Combinations of the foregoing with estradiol itself can be used (eg, a combination of estradiol and estradiol-17-valerate or more a combination of estradiol-17-valerate and estradiol-3, 17-divalerate) with beneficial results. . For example, 15-80% of each compound can be used based on the total weight of the estrogenic steroid component to obtain the desired result. Other combinations can also be used to obtain the desired absorption and levels of 17 p-estradiol in the body of the subject being treated.

[0063] It will be appreciated that hormones can be used not only in the form of pure chemical compounds, but also in a mixture with other pharmaceutical products that can be applied transdermally or with other ingredients that are not incompatible with the desired objective as it has been listed above. Therefore, simple pharmacologically acceptable derivatives of hormones such as ethers, esters, amides, acetals, salts and the like can be used, if appropriate. In some cases, such derivatives may be preferred. The progestin compound and the estrogenic steroid are generally dispersed or dissolved simultaneously in the manufacture of the adhesive polymer matrix containing hormones or can be dispersed or dissolved separately.

[0064] The polymers used as active patch components: The layer IA it contains may be a polymer matrix comprising the pharmaceutically or cosmetically active ingredient. The polymer can be a PSA to form a biologically acceptable adhesive polymer matrix, preferably capable of forming thin films or coatings through which AI can pass at a controlled rate. Suitable polymers are biologically and pharmaceutically compatible, non-allergenic, insoluble and compatible with body fluids or tissues with which the device is contacted. The use of water-soluble polymers is generally less preferred since dissolution or erosion of the matrix would affect the rate of AI release, as well as the ability of the dosing unit to remain in place in the skin. Therefore, in certain embodiments, the polymer is not soluble in water.

[0065] Preferably, the polymers used to form a polymer matrix in the IA-containing layer have glass transition temperatures below room temperature. The polymers are preferably non-crystalline, but may have some crystallinity if necessary for the development of other desired properties. Cross-linked monomer units or sites can be incorporated into such polymers. For example, crosslinking monomers that can be incorporated into polyacrylate polymers include polymethacrylic esters of polyols, such as butylene diacrylate and dimethacrylate, trimethyl ethyl propane trimethacrylate and the like. Other monomers that provide such sites include allyl acrylate, allyl methacrylate, diallyl maleate and the like.

[0066] In certain transdermal drug delivery devices, there is a permeable or breakable barrier, a velocity control membrane or the like interposed between the material containing AI and the release liner, so that when the liner is removed from release, said barrier remains in place. The purpose of such a barrier can be, for example, to prevent the material containing AI from leaving the device or to control the rate of absorption by the skin. In the device used to generate the data illustrated in Figure 1, there is no need for a layer between the release liner and the IA layer because the polymer matrix adheres to the remaining layers of the device and does not flow easily and because the matrix It is designed to administer the right medication through the skin without restricting the flow. Therefore, the polymer matrix adheres directly to the release liner and, after administration to the skin, the polymer matrix adheres directly to the skin throughout the entire surface area of the exposed AI layer by the removal of the release liner.

[0067] A useful adhesive polymer formulation comprises a polyacrylate adhesive polymer of the general formula (I):

wherein "X" represents the number of repetitive units sufficient to provide the desired properties in the adhesive polymer and R is H or a lower (C1-C10) alkyl, such as ethyl, butyl, 2-ethylhexyl, octyl, decyl and the like . More specifically, it is preferred that the adhesive polymer matrix comprise a copolymer of polyacrylate adhesive having a 2-ethylhexyl acrylate monomer and about 50-60% w / w vinyl acetate as a co-monomer. An example of a polyacrylate adhesive copolymer suitable for use in the present invention includes, but is not limited to, the one sold under the trade name of Duro Tak 87-4098 by National Starch and Chemical Co., Bridgewater, NJ, comprising a certain percentage of vinyl acetate comonomer.

[0068] Moisturizer / plasticizer: Preferably, a plasticizer / humectant is dispersed within the adhesive polymer formulation. The incorporation of a humectant into the formulation allows the dosage unit to absorb moisture from the skin's surface, which in turn helps reduce skin irritation and prevents the adhesive polymer matrix from the administration system from failing. The plasticizer / humectant may be a conventional plasticizer used in the pharmaceutical industry, for example, polyvinylpyrrolidone (PVP). In particular, PVP / vinyl acetate (PVP / VA) copolymers, such as those having a molecular weight of approximately 50,000, are suitable for use in the present invention. The pVp / VA acts as a plasticizer, which acts to control the stiffness of the polymer matrix, and as a humectant, which regulates the moisture content of the matrix. The PVP / VA can be, for example, PVP / VA S-630, which is a PVP: VA 60:40 co-polymer having a molecular weight of 51,000 and a glass transition temperature of 110 C. The amount of humectant / plasticizer is directly related to the duration of adhesion to cover. The PVP / vinyl acetate can be PVP / VA S-630 supplied by International Specialty Products, Inc. (ISP) of Wayne, New Jersey, where the PVP and vinyl acetate are each present at approximately the same percentage in weight.

[0069] The shape of the device of the invention is not critical. For example, it can be circular, that is, a disk, or it can be polygonal, for example, rectangular or elliptical. The surface area of the AI layer generally should not exceed 60 cm2 area. Preferably, it will be about 5 to 50 cm2, more preferably, about 8 to about 40 cm2. Most preferably, the discs will be from about 10 to about 20 cm2. A 15 cm2 disc may be preferred because it is relatively small, but may be able to disperse high levels of hormones.

[0070] Therefore, a useful illustrative matrix of polymers comprising hormones useful for delivering an effective amount of a progestin and an estrogen in amounts effective to prevent pregnancy according to the method of the invention comprises a polyacrylate adhesive copolymer. with about 3% to about 60% w / w vinyl acetate and, as a percentage by weight of the adhesive polymer matrix:

a) from about 15% to about 35% PVP / VA;

b) from about 10% to about 30% of a combination of skin permeation enhancing agents, which is a mixture comprising from about 4% to about 12% DMSO, from about 4.2% to about 12, 6% lauryl lactate, about 0.7% to about 2.3% ethyl lactate, and about 3% to about 9% capric acid; Y

c) from about _6% to about 1.2% of LNG and EE, for example, about 87% of LNG and about, 77% of EE.

The inner backing layer

[0071] An internal backing layer can be made of any suitable material that is impermeable or substantially impermeable to AI and to the excipients of the adhesive polymer matrix. The inner backing layer serves as a protective cover for the IA layer and provides a support function. The backing layer may be formed so that it is essentially the same size as the adhesive polymer matrix containing hormones or may have a larger dimension so that it can extend beyond the edges of the patch containing AI outwards. The backing layer may have any appropriate thickness that provides the desired protection and support functions. A suitable thickness is from about 10 to about 300 microns. More specifically, the thickness is less than about 150 microns, but more specifically, it is less than about 100 microns, and more specifically, the thickness is less than about 50 microns.

[0072] Examples of suitable materials for manufacturing the inner support layer are polypropylene films, polyesters such as polyethylene terephthalate, metal sheets, metal sheet laminates of such suitable polymer films and the like. Polyester films, such as Mylar® (DuPont Teijin) and Scotchpak® 9732 (3M Company), are particularly suitable for use in the present invention.

Release liner

[0073] The surface area of the release liner is larger than that of the AI layer. This can be seen in Figure 3, where the diameter (in the case of a round device) or the width and length (in the case of a polygonal device) of Layer 3 is greater than that of Layers 5 and 6 , so that it extends beyond the IA layer in some or all directions.

[0074] The release liner is made of any material (1) that is impermeable or substantially impermeable to the components of the AI layer, (2) to which the PSA in the overlay will adhere, as discussed further below. , and (3) this can be easily removed by detaching it from the AI layer and superimposing the PSA just before applying it to the skin.

[0075] The release liner may have the same dimensions as the overlay, discussed below, or it may extend fully or partially beyond the edge of the patch. In one embodiment, the release liner extends partially beyond the liner to form "tabs" of release liner material that extend beyond the edges of the liner for easy separation of the liner from the rest of the system.

[0076] A fluorinated or siliconized polyester sheet or other fluorinated or siliconized polymer such as a polyacrylonitrile copolymer, or a sheet coated with a siliconized or fluorinated polymer may be comprised. The release liner is preferably not polystyrene because it has been shown that polystyrene will absorb DMSO. A preferred material for the release liner when the cover layer 4a comprises a PSA GDP is a Scotchpak® (3M Company) liner, such as the Scotchpak® 1022 or Scotchpak® 9744 fluorinated polyester release coatings.

Overlap

[0077] The overlay comprises a PSA in which the solubility of volatile components is less, preferably significantly less, than the solubility of those same components in the AI matrix. Then, for example, when the volatile component is DMSO or ethyl lactate, a PSA GDP can be chosen. With reference to Fig. 2, the GDP layer ^p S ^a is Layer 3. Generally, said PSA GDP comprises a mixture of a low to medium molecular weight and a high molecular weight GDP, a plasticizer such as polybutene and a hydrocolloid such as a cross. Linked polyvinylpyrrolidine. Useful GDP includes, for example, the GDP of Oppanol® (BASF), which have average molecular weights between 40,000 and 4,000,000.

[0078] A useful PSA GDP comprises crospovidone such as Kollidon® CLM crospovidone (BASF) (for example, 5-45% by weight, preferably 15-30% by weight, and more preferably 20-25% by weight); a low viscosity GDP, such as Oppanol® B12 (molecular weight: 51000, viscosity at 150 C: 150 Pascal-seconds) (for example, 10-60% by weight, preferably 30-50% by weight); a high viscosity GDP, such as Oppanol® B100 (viscosity: approximately 1100 Pascal-seconds) (for example, 2-15% by weight, preferably 5-15% by weight); a polybutene such as Indopol® 1900 (Innovene LLC) (molecular weight: 2500, viscosity at 100 C: 3900-4200 centistokes) (for example, 10-60% by weight, preferably 20-40% by weight); and a mineral oil (0-20% by weight). For example, an illustrative formulation comprises about 20% by weight of crospovidone, about 40% by weight of a low viscosity GDP, about 8% by weight of a high viscosity GDP and about 32% by weight of polybutene. (The term "about" as used in this specification means more or less 10%. "Low viscosity" means less than about 300 Pascal-seconds and "high viscosity" means more than about 800 Pascal-seconds , when the viscosity is measured at 150 ° C) The cross-linking of the PVP is useful because the crosslinked polymers tend to be swellable in water but insoluble in water. Said PSA GDP can provide good wear stability, for example, fixation in normal living conditions for at least 7 days. Said PSA GDP can provide good wear stability, for example, fixation in normal living conditions for at least 7 days. Said PSA GDP can provide good wear stability, for example, fixation in normal living conditions for at least 7 days.

[0079] Other rubber-based polymers that may be used instead of PSA GDP in the overlay include silicone-based PSAs, such as BIO-PSA® (Dow Corning); copolymers and terpolymers of styrene / butadiene / styrene, styrene / isoprene / styrene and styrene-ethylene-butyl styrene, such as Kraton D styrene / butadiene and Kraton G styrene-ethylene / butylene-styrene or styrene Rubbers of isoprene can also be used, such as Kraton IR linear polyisoprene homopolymers.

[0080] As shown in Fig. 2, and as the release liner, the overlay can extend beyond the perimeter of the AI layer in all directions, typically by a range of about 0.1 to about 1 , 5 cm, more specifically from 0.3 to about 1.2 cm, and even more specifically from about 0.8 cm beyond the perimeter of the IA layer.

[0081] Overlapping, if it comprises a PSA layer, improves skin adhesion by complementing the adhesion provided by PSA in the AI layer, if present, or, in the case of an AI layer that does not It comprises a PSA, provides adhesion to the skin.

[0082] In addition, the overlay adheres to the release liner around the perimeter of both layers, thereby sealing the components of the AI layer. By correctly selecting the materials comprising the liner and release liner, this seal between them avoids, or substantially avoids, the The volatile component escapes into the AI layer, but still allows the user to easily remove the release liner before topical application.

[0083] The sealing is formed in situ by mechanically pressing together the edges of the overlay that extend beyond the perimeter of the AI layer and the edges of the release liner that extend beyond the perimeter of the AI layer. When the first coating layer is a PSA GDP and the release liner is a fluorinated or siliconized polyester film, a suitable seal made by pressure can be placed. The amount of pressure required to form such a seal is not critical. Finger pressure is adequate. Of course, in an illustrative embodiment of the invention, it is desirable that the seal can be broken by peeling the release liner from the rest of the system by hand just before application to the skin.

[0084] The seal between the overlay PSA and the release liner prevents, or substantially prevents, the loss of the components of the AI layer through the seal between these two layers, such as during system storage . The seal is preferably "tight" to the inner backing layer and the AI layer, so that there is minimal or no filtration of the polymer matrix in the spaces between the overlay and the release liner or between the overlay and the Internal backing layer or AI layer.

[0085] The overlay may also comprise a cover (1) that does not comprise a PSA, that is, that comprises a non-PSA layer, such that the surface of the layer that is exposed to fingers, clothing and dirt environment or dust is not sticky, it is flexible or malleable to flex with the movements of the skin and muscles, it is of a color and texture that is not noticeable or attractive, and allows skin moisture to pass through the device due to which is porous or water permeable.

[0086] Therefore, it may be desirable to use a multi-layer overlay comprising a first layer of a PSA in which the volatile component is insoluble, covered with an intermediate layer and a covering layer having the properties described above. Said illustrative overlay is illustrated in Fig. 2 as Layers 1, 2 and 3.

[0087] While a PSA GDP is useful for containing DMSO or ethyl lactate, or both, in the AI layer, the PSA GDP can flow through most of the overlay coatings that have the properties described above. Such a PSA GDP flow can cause the device to become sticky and discolored. Therefore, it may be desirable to use a cover covering comprising two layers, one of which is a polymeric layer interposed between the PSA GDP (an intermediate layer) and a support layer. Said intermediate layer may be a polyacrylate PSA as described above, because said PSA will substantially prevent the flow of PSA GDP to and through the coating cover, but will not migrate substantially by itself through the coating cover.

[0088] The overlay is a laminate comprising three layers: a PSA GDP layer; (3, in Fig. 2); an intermediate layer comprising a material that does not allow the flow of the PSA GDP but allows the passage of moisture (2, in Fig. 2); and a cover covering (or backing layer) that is not sticky, attractive, flexible and moisture permeable (1, in Fig. 2).

[0089] Materials useful in the intermediate layer include, for example, polyacrylates, polyurethanes, plasticized polyvinyl chloride and copolymers of polyethylene and ethyl vinyl acetate. Rubber-based polymers having a very high molecular weight, for example, can also be used at least about 150,000 Daltons, as can rubber-based polymers that can be crosslinked. Examples include Kraton D styrene / butadiene, IR linear polyisoprene homopolymers that are crosslinkable can also be used. The intermediate layer may comprise a PSA that joins the first overlay layer, as well as the overlay coverage. Crosslinked polymers of high molecular weight are preferred. Preferably, said PSA is a polyacrylate as described above with reference to the AI layer.

[0090] The materials used in the overlay coating are not PSA. They include, for example, a polyurethane film, foam or spunbonded structure, a polyolefin foam, a PVC foam or a woven or nonwoven fabric. Illustrative fabrics include KOB 051, 053 and 055 (Karl Otto Braun) polyester polyesters. Illustrative nonwoven fabrics include polyesters. An illustrative polyurethane material is the CoTran ™ 9700 (3M) molten polyurethane nonwoven backing, which can be colored in skin tones. Suitable materials are described, for example, as backing layers in US 6,660,295.

[0091] If the overlay cover is not porous, then it can be used without an intermediate layer. However, if the coating cover is not porous, adhesion problems may arise due to the accumulation of moisture at the skin interface / PSA GDP. A solid material can be used, that is, one that is not porous, but that is otherwise permeable to water, such as a thin polyurethane film, for example, 1 mil (ie, 0.001 inches). However, a porous material such as a foam or cloth, in general, will better retain its shape and provide good adhesion.

[0092] The present invention is not limited to the embodiments described and exemplified above, but is capable of variations and modifications within the scope of the appended claims.

Claims (13)

1. A contraceptive method, comprising: (A) consecutively apply three transdermal hormone treatment devices on a woman's skin for a 3 week treatment interval, applying each device for 1 week, and each device comprises an effective amount of a progestogen and an estrogen followed by a 1 week rest interval; Y (B) applying a resting interval device for at least a portion of the resting interval, in which the resting interval device comprises low dose progestin and low dose estrogen. 2. A method of contraception according to claim 1, wherein (i) the amount of estrogen is the same in all treatment devices, or (ii) the amount of progestin is the same in all treatment devices , or (iii) the amount of progestin is the same in all treatment devices and the amount of estrogen is the same in all treatment devices. 3. A contraceptive method according to claim 1 or claim 2, wherein the method results in an average serum progestin concentration equivalent to at least about 750 pg / ml of levonorgestrel during the treatment interval, optionally excluding all or a part of the first cycle of treatment, in a given subject or in a population of subjects; optionally, in which the method produces an average serum concentration of progestin equivalent to at least about 500 pg / ml of levonorgestrel during week 1 of the treatment interval, in a given subject or in a population of subjects; optionally, where the method results in an average serum progestin concentration equivalent to at least about 750 pg / ml of levonorgestrel during week 2 and week 3 of the treatment interval, in a given subject or in a population of subjects. 4. A method of contraception according to any of the preceding claims, wherein the method results in an average serum estrogen concentration equivalent to about 15 to about 65 pg / ml ethinylestradiol during each treatment interval, in a subject given or in a population of subjects; optionally, wherein the method results in an average serum estrogen concentration equivalent to about 20 to about 30 pg / ml ethinylestradiol during the entire treatment interval, in a given subject or in a population of subjects. 5. A method of contraception according to any of the preceding claims, wherein the transdermal hormone delivery devices comprise a support layer and an adhesive polymer matrix comprising a mixture of an adhesive polymer, a progestin, an estrogen and one or more skin permeation enhancers; optionally, in which the devices comprise levonorgestrel and ethinyl estradiol; optionally, wherein one or more skin permeation enhancers comprise an organic solvent; optionally wherein the skin permeation enhancers comprise a combination of a pharmaceutically acceptable organic solvent, a fatty (C8-C20) alcohol ester of a hydroxy acid, a lower (C1-C4) alkyl alkyl ester of an acid hydroxyl, and a C6-C18 fatty acid. 6. A method of contraception according to any one of the preceding claims, wherein (i) the progestin is levonorgestrel or (ii) the estrogen is ethinyl estradiol, or (iii) the progestin is levonorgestrel and the estrogen is ethinyl estradiol. 7. A method of contraception according to any of the preceding claims, wherein the method results in a maximum serum hormone concentration during the period of time in which a single treatment device of at least about 1 is used, 1 times the minimum level, but no more than about twice the minimum level, or no more than about 1.8 times the minimum level, or no more than about 1.5 times the minimum level, or no more than about 1, 25 times the minimum level, after the first week of the treatment interval, in a given subject or in a population of subjects; optionally, wherein the method results in a maximum serum hormone concentration during the period of time in which a single treatment device of at least about 1.25 times the minimum level is used, but not more than about twice the level minimum, or not more than about 1.8 times the minimum level, or not more than about 1.5 times the minimum level, after the first week of the treatment interval, in a given subject or in a population of subjects. 8. A method of contraception according to any one of the preceding claims, wherein the rest interval device comprises low dose progestin and low dose estrogen in amounts effective to attenuate the symptoms of menstruation. 9. A method of contraception according to any one of the preceding claims, wherein the amount of hormones administered during the rest interval is not more than 80% of the amount administered during the treatment interval. 10. The method of contraception according to any of the preceding claims, wherein the amount of hormones administered during rest intervals is 3/4, 2/3, 1/2, 1/3 or 1/4 of the amount administered for an equivalent time during the treatment interval. 11. A method of contraception according to any one of the preceding claims, wherein the rest interval device is performed in the same manner as the treatment device, but with a reduced amount of hormones. 12. A method of contraception according to claim 10, wherein the amount of hormones is reduced (i) by reducing the size of the device, or (ii) by reducing the amount of hormones and / or enhancers. 13. A kit comprising: (a) 3, or a multiple of 3, transdermal hormone administration treatment devices, each treatment device comprises a progestin and an estrogen in amounts sufficient to reduce the risk of pregnancy, and each device is designed to be used for 1 week. ; (b) 1, or the same multiple of 1, rest interval devices, each rest interval device comprising low dose progestin and low dose estrogen; and (c) instructions for use in a 28-day treatment cycle.